Benzhydryl ethers of tropine and processes of preparation



United States Patent BENZHYDRYL ETHERS OF TROPINE AND PROCESSES OFPREPARATION John Weijlard, Maplewood, N. J., assignor to Merck & Co.,Inc., Rahway, N. L, a corporation of New Jersey No Drawing. ApplicationMarch 29, 1952, Serial No. 279,475

6 Claims. (Cl. 260-292) This invention relates to tropine benzohydrylethers; more particularly it is concerned with a novel process for thepreparation of tropine benzohydryl ethers and acid salts thereof.

The copending application, Serial No. 76,183, filed February 12, 1949,now United States Patent No. 2,595,405, issued May 6, 1952, describes aprocess of preparing tropine benzohydryl ether which comprises reactingtropine with diphenyldiazomethane. This method is not particularlysatisfactory for the preparation of tropine benzohydryl ether on acommercial scale since the reaction is potentially dangerous in view ofthe unstable and explosive nature of diphenyldiazomethane. Further,diphenyldiazomethane is not available commerorally and must be preparedby processes which are hazardous to carry out on a commercial scale,such as the reaction of benzophenone hydrazone with yellow mercuricoxide in petroleum ether. Thus, a more satisfactory method of preparingtropine benzohydryl ether has been sought.

The object of this invention is to provide a process for the preparationof tropine benzohydryl ethers which can be readily and convenientlycarried out on a commercial scale and Will avoid the hazards involved inthe use of diphenyldiazomethane. Other objects of the invention will beapparent from the detailed description hereinafter provided.

In accordance with my invention, the desideratum is achieved byintimately contacting tropine with a diphenylhalomethane in an acidicmedium to form the desired tropine benzohydryl ether. Thus, the reactionfor the preparation of tropine benzohydryl ether may be shown asfollows:

CH:-CH--CH: H Acidic medium CH: HOH+ C(CsHsh Hr- H H: X

CHz-CH-CHz N-CH: CHOCHJCoHsM CHa- H- H2 wherein X represents a halogen.

Similarly, substituted diphenylhalomethanes may be reacted with tropinein 'an acidic medium in place of diphenylhalomethane to obtain thecorresponding substitutcd tropine benzohydryl ethers. Thus,diphenylhalomethanes of the formula wherein X is a halogen and R and R1are nuclear phenyl substituents from the group consisting of hydrogen,halogen, lower alkoxy and lower alkyl, can be reacted with tropine toobtain the corresponding tropine benzo hydryl ethers. Suitable startingmaterials that might be mentioned include 4-chlorodiphenylbromethane,4,4- dichlorodiphenylchloromethane, 4-methyldiphenylhromo- 2,706,198Patented Apr. 12, 1955 methane, 4,4'-dimethyldiphenylbromomethane,4-methoxydiphenyliodomethane, 4,4-dimethoxydiphenylbromomethane,4-ethyldiphenylbromomethane, 4,4'-diethoxydiphenylchloromethane, 4propyldiphenylbromomethane, 2-ethoxydiphenylchloromethane,2,2'-dipropoxydiphenylbromomethane, 3-methyldiphenylbromomethane, 3,3-dimethoxydiphenylbromomethane, 2,2-dichlorodiphenylbromomethane,3-bromodiphenylbromomethane, 3,3-diiododiphenylbromomethane, and thelike.

In effecting this condensation, I find that it is most convenientlyaccomplished by dissolving the tropine in a suitable acidic medium,adding the diphenylhalomethane thereto, and permitting the reactionmedium to stand at room temperature for sufiicient time to complete thereaction. The lower aliphatic carboxylic acids, and in particular aceticacid which is inexpensive and readily available, are especially suitableas acidic reaction mediums for carrying out this condensation. Althoughany of the diphenylhalomethanes may be employed in my process, I havefound the bromomethanes to be particularly satisfactory in this reactionand most readily prepared. Diphenylbromomethane is availablecommercially or it may be readily prepared as described in Berichte, 43,2940 (1910) or Ann., 442, 245 (1925).

Thus, in accordance with a preferred embodiment of my invention, theprocess of my invention is effected by adding an amount of adiphenylbromomethane slightly in excess of the quantity theoreticallynecessary, to a solution of tropine dissolved in glacial acetic acidobtained by warming the tropine in glacial acetic acid to effectsolution and then cooling the solution to about 20 C. The resultingreaction mixture is allowed to stand at room temperature with occasionalstirring to permit the condensation of the reactants. Generally, I findit desirable to allow the reaction mixture to stand for about four daysor more to achieve maximum yields under optimum conditions. Further, Ifind it preferable to carry out the reaction at room temperaturealthough higher temperatures up to about C. may also be employed.Temperatures in excess of about 90 C. are usually undesirable since Ifind that higher temperatures result in decreased yields of the desiredproduct.

The use of an acidic solvent in effecting the condensation appears to benecessary in order to avoid the formation of undesirable quaternaryammonium compounds since the use of neutral solvents such as etherorbenzene results in the formation of the quaternary ammonium compoundin almost quantitative yield.

Various methods can be utilized to recover the formed tropinebenzohydryl ether from the reaction mixture after the condensation iscompleted. I have found that this is most conveniently accomplished byisolating the desired product as the hydrobromide salt. This can bereadily accomplished by adding water, ether and finally an aqueoussolution of hydrobromic acid to the reaction mixture containing thetropine benzohydryl ether. The product is precipitated as thehydrobromide salt by the addition of water, ether and an aqueoussolution of the hydrobromic acid, and may be recovered by filtration. Ifdesired, the product so obtained can be further purified byrecrystallization from a suitable solvent such as ethyl alcohol.

The acid salts of the tropine benzohydryl ethers have anti-histamine andatropine-like activity. These saltsmay be readily converted to tropinebenzohydryl ether methane sulfonates which are very soluble in water andalso possess anti-histamine and atropine-like activity by methods knownin the art.

The following examples are presented to illustrate the novel process ofmy invention.

Example 1 the resulting syrup distilled in vacuum at -119 C. at 8 mm.pressure.

To a solution of 21.1 g. (0.15 mole) of distilled tropine base dissolvedin 75 cc. of glacial acetic acid by warming and then cooling thesolution to 20 C. was added 40 g. (0.16 mole) of diphenylbromomethane.The resulting mixture was allowed to stand for 96 hours at roomtemperature and agitated by stirring once or twice a day.

To the reaction mixture was added 300 cc. of ether and 300 cc. of waterfollowed by 25 cc. of 40% hydrobromic acid. The resulting mixture wasagitated vigorously and allowed to stand an hour at room temperature.The precipitated tropine benzohydryl ether hydrobromide was then removedby filtration and the product washed with 4 x 50 cc. of ether, and then4 x 50 cc. of water, and the resulting crude product air dried at 4550C. The yield of tropine benzohydryl ether hydrobromide was 39.3 g.(67.5% theory). The product had a melting point of 24l243 C. and a mixedmelting point with a known sample of tropine benzohydryl etherhydrobromide was not depressed.

The crude tropine benzohydryl ether hydrobromide so obtained waspurified by suspending 62 g. of the crude product in 620 cc. of alcohol,heating the resulting solution to boiling, and then cooling to C. Theprecipitated tropine benzohydryl ether hydrobromide was then filteredoff, washed with 2 x 50 cc. of ice cold alcohol and air dried at 45-50C. The product so obtained was found to melt at 25025 1 C.Analysis.Calcd. for C21H2sONBr: C, 64.95; H, 6.75; N, 3.60. Found: C,64.74; H, 6.63; N, 3.61.

Example 2 Time, hours Yield, percent Example 3 To a solution of 21.1 g.(0.15 mole) of distilled tropine base in 75 cc. of glacial acetic acidat C. was added 50.6 g. (0.16 mole) of 4,4-dichlorodiphenylbromomethane(M. P. 6769 C.), which may be prepared as described in J. A. C. S. 42,2091 (1920). The resulting reaction mixture was allowed to stand at roomtemperature for 113 hours. To this solution was then added 200 cc. ofether precipitating tropine hydrobromide as an oil which sooncrystallized to a fine white powder. On recrystallizing this productfrom ethanol it was found to melt at 264265.5 C. with decomposition.

The ethereal mother liquors on standing in the refrigerator for about 10days deposited crystals of tropine 4,4'-dichlorobenzohydryl etherhydrobromide. On recrystallization from hot ethanol the product wasfound to melt at 242.5-243.5 C. with decomposition.

Analysis.Calculated for C21H24ONCl2Br: C, 55.10; H, 5.30; N, 3.06; Br,17.4. Found: C, 55.06; H, 5.09; N, 3.28; Br, 17.0.

Various changes and modifications may be made in my invention, certainpreferred embodiments of which are herein disclosed, without departingfrom the scope thereof; to the extent that these changes andmodifications are within the scope of the appended claims, they are tobe considered as part of my invention.

I claim:

1. The process which comprises reacting tropine withdiphenylbromomethane in acetic acid to form tropine benzohydryl ether.

2. The process which comprises reacting tropine with4,4'-dichlorodiphenylbromomethane in acetic acid to form tropine4,4'-dichlorobenzohydryl ether.

3. The process which comprises reacting tropine withdiphenylbromomethane in a lower aliphatic carboxylic acid to formtropine benzohydryl ether.

4. The process which comprises reacting tropine with4,4-dichlorodiphenylbromomethane in a lower aliphatic cirfiboxylic acidto form tropine 4,4-dichlorobenzohydryl e er.

5. The process which comprises reacting tropine with4,4-dichlorodiphenylhalomethane in a lower aliphatic cafiboxylic acid toform tropine 4,4-dichlorobenzohydryl et er.

6. The process which comprises reacting a diphenylhalomethane of theformula:

wherein R and R are substituents from the group consisting of hydrogen,halogen, lower alkoxy and lower alkyl and X is a halogen with tropine inthe presence of a lower aliphatic carboxylic acid to form a tropinebenzohydryl ether of the formula:

CHz-CH-CH2 NCH: 21110-4311 CHr- H- E:

wherein R and R are the same as defined above.

References Cited in the file of this patent UNITED STATES PATENTS2,453,729 Rieveschl, Jr. Nov. 16, 1948 2,454,092 Rieveschl, Jr. Nov. 16,1948 2,508,499 Cusic May 23, 1950 2,567,350 Rieveschl, Jr. Sept. 11,1951 2,567,351 Rieveschl, Jr. Sept. 11, 1951 2,595,405 Phillips May 6,1952

6. THE PROCESS WHICH COMPRISES REACTING A DIPHENYLHALOMETHANE OF THEFORMULA: